UNIVERSITY OF PENNSYLVANIA ALZHEIMER?S DISEASE CORE CENTER ABSTRACT: REVISION TO CREATE A NEW GENETICS CORE (CORE H) ADCC Director and Principal Investigator: John Q. Trojanowski, MD, PhD Genetics Core Leader: Vivianna Van Deerlin, MD, PhD; Co-Leader: Gerard Schellenberg, PhD This is an application for a revision of the University of Pennsylvania (Penn) Alzheimer Disease Core Center (ADCC) to establish an independent Genetics Core (Core H). We propose to create a Genetics Core which will enhance and expand the genetics activities of the Penn ADCC. The focus of the Penn ADCC is to develop a mechanistic understanding of the still evolving complexity of Alzheimer disease (AD) and related dementias (ADRD) by studying the spectrum of disease from earliest onset through progressive stages of disease and ultimately at autopsy. Genetic factors play a critical role in the risk for AD as well as related dementias (RD) including Lewy body dementia and frontotemporal degeneration, which share common mechanisms of neurodegeneration with AD. Furthermore, many patients have more than one clinical or pathologic phenotype and 20-30% of patients with a clinical diagnosis of AD do not have AD pathology, but instead represent a RD. Therefore, the proposed Genetics Core will support the mission of the Penn ADCC by providing the necessary resources, including the leadership and genetics expertise of Vivianna Van Deerlin and Gerard Schellenberg, to conduct and support molecular genetics research of ADRD in collaboration with the existing Cores. To this end, the Specific Aims of Core H are to: 1) Serve as a repository for DNA collected from Clinical Core B participants and autopsy brains characterized in Neuropathology Core D. Collected samples will undergo quality control and ancestry measures and will be available for use by Penn investigators and external collaborators, including shipment to NCRAD; 2) Genotype risk factor variants associated with ADRD in the Clinical Core B cohort of ADRD, MCI, and control subjects to use in Penn studies as covariates, including APOE and other previously identified risk factor loci using a variety of approaches. In addition, perform genetic analysis of genes associated with hereditary neurodegenerative diseases in ADRD subjects; 3) Serve as a centralized resource for storage and handling of genetic and sample data in conjunction with the Data Management, Bioinformatics and Biostatistics Core C; 4) Contribute to patient and community education efforts of the Outreach and Recruitment Core E by providing genetic counseling services to Clinical Core B participants and to training activities of Research Education Core F as they relate to genetics and biospecimen collection education. In summary, this proposed Genetics Core H will interact with all existing cores as well as the recently submitted Biomarker Core G thereby augmenting the genetics activities and extending the aims of the Penn ADCC as a whole.